Efficacy of pembrolizumab and comprehensive CD274/PD-L1 profiles in patients previously treated with chemoradiation therapy as radical treatment in bladder cancer

Abstract

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial carcinoma, although it is unknown whether the efficacy of pembrolizumab in patients previously treated with curative CRT varies from the results of benchmark trials.MethodsWe retrospectively assessed whether the survival benefit of pembrolizumab differs between patients previously treated with TC or CRT as radical treatment. A total of 212 patient records were collected for a logistic regression propensity score model. An independent dataset with next-generation sequencing (n=289) and PD-L1 Combined Positive Score (CPS: n=266) was analyzed to assess whether CRT-recurrent tumor harbors distinct CD274/PD-L1 profiles.ResultsPropensity score matching was performed using putative clinical factors, from which 30 patients in each arm were identified as pair-matched groups. There was no significant difference in overall survival from the initiation of pembrolizumab (p=0.80) and objective response rate (p=0.59) between CRT and TC treatment groups. In the independent 289 BC cohort, 22 samples (7.6%) were collected as CRT-recurrent tumors. There was no significant difference in CD274 mRNA expression level between CRT-naïve and CRT-recurrent tumors. The compositions of CD274 isoforms were comparable among all isoforms detected from RNAseq between CRT-naïve (n=267) and CRT-recurrent (n=22) tumors. No actionable exonic mutation in CD274 was detected in CRT-recurrent tumors. PD-L1 CPS was positively correlated with CD274 mRNA expression level, and PD-L1 CPS was comparable between CRT-naïve and CRT-recurrent tumors.ConclusionsThe efficacy of pembrolizumab for patients previously treated with CRT was similar to those treated with TC. The enhanced tumor regression by combining programmed cell death protein 1/PD-L1 inhibitor and CRT might be expected only in the concurrent administration.

Concurrent palliative radiation with pembrolizumab for platinum-refractory urothelial carcinoma is associated with improved overall survival

“…The Median OS of each group was 4.5 months for the sequential SBRT group and 12.0 months for the concomitant SBRT group. We recently reported that the clinical effect of pembrolizumab for mUC patients previously treated with curative chemo-radiation therapy, whose tumor might have increased tumor mutation burden, has no additional survival benefit [24] , [25] . Collectively, given that our findings showed an improved OS in the concurrent radiation therapy for patients treated with pembrolizumab, the enhanced effect of pembrolizumab caused by the radiation therapy should be expected only in the concurrent administration.…”

Prognostic Role of Systemic Inflammation Indexes in Metastatic Urothelial Carcinoma Treated With Immunotherapy

“…Blood tests were conducted in different laboratories. Finally, the PD-L1 status of these patients was not investigated [ 27 ].…”

Tertiary lymphoid structure and neutrophil–lymphocyte ratio coordinately predict outcome of pembrolizumab

“…Ideally, in this context, collecting chemo‐resistant tumor samples just before starting pembrolizumab treatment would be the most appropriate approach, although this is impractical in the current clinical practice. Second, other major immune‐modulating players including PD‐L1 and TMB were not evaluated in the study 21,22 . Finally, robust validation of these biomarkers in prospective trials across different cancer types and CPIs regimens is required.…”

“…Second, other major immune‐modulating players including PD‐L1 and TMB were not evaluated in the study. 21 , 22 Finally, robust validation of these biomarkers in prospective trials across different cancer types and CPIs regimens is required. Further studies with large and prospective settings are warranted to prove the present findings.…”